From Gene Discovery to Preventing Eye Disease in Retinitis Pigmentosa.

March 23, 2005.
University of Pennsylvania Medical Center.

Retinitis pigmentosa (RP) is an inherited eye disease that causes visual disability leading to blindness. Over the last 15 years, researchers have pinpointed defects in dozens of genes causing different forms of RP. Surprisingly, patients with the same genetic defect can show different severities of vision loss and rates of disease progression. This effect is most dramatic across the retina of some individuals where regions with normal vision can abut regions of no vision. Environmental factors have been near the top of the suspect list for this variation in severity. An environmental factor experienced by all, but to varying extents, is exposure to light - bright lights have been previously speculated to accelerate certain forms of RP.

Now, investigators from the University of Pennsylvania and Cornell University provide evidence for retinal injury caused by moderate light exposure in dogs with a mutation in the rhodopsin gene. Since the blindness in these dogs mimics that observed in human RP caused by mutations in the rhodopsin gene, the investigators strongly recommend limiting excess light exposure in these patients.

“Rhodopsin is the light-catching molecule within rod photoreceptor cells that afford us with night vision,” says Artur V. Cideciyan, PhD, Research Associate Professor of Ophthalmology at Penn's Scheie Eye Institute, and lead author of the current study published online this week in the Proceedings of the National Academy of Sciences.

“About 100 mutations in the rhodopsin gene have been shown to cause RP but our understanding of the steps between mutant proteins and death of rod photoreceptors remains incomplete,” says Cideciyan. “What we know is that there are at least two ways in which rhodopsin mutations lead to blindness. Some mutations destroy vision in early life and children are left with only impaired day vision, which then disappears. In other mutations, night vision can be present throughout life but has a characteristically slowed recovery time in the dark. Decline of vision is gradual. Naturally occurring rhodopsin mutant dogs that we studied mimic the latter type of human disease.”

Cideciyan and colleagues Samuel G. Jacobson, MD, PhD, the F.M. Kirby Professor in Penn's Department of Ophthalmology and Director of the Center for Hereditary Retinal Degenerations at Scheie, Gustavo D. Aguirre, VMD, PhD, Professor of Medical Genetics and Ophthalmology at Penn's School of Veterinary Medicine, and Gregory M. Acland, BVSc, of Cornell University asked whether modest light levels cause damage to retinas of the rhodopsin mutant dogs. The investigators performed the routine clinical procedure of retinal photography in the dogs. Normal dogs had no ill effects of the procedure. Surprisingly, the mutant dogs had complete degeneration one month after retinal photography and only in those regions that were photographed. There were no abnormalities associated with neighboring regions of the retina that were not photographed. Further experiments with focal light exposures and cross-sectional retinal imaging showed that retinal injury was detectable within 30 minutes and c ould cause complete retinal degeneration within a month following these moderate lights.

“Rhodopsin mutant dogs are one of several naturally occurring canine retinal degenerations which duplicate human hereditary eye diseases,” comment Aguirre and Acland, who have spent more than 20 years identifying and investigating inherited veterinary retinal degenerations and their treatments. “Identifying a light-induced component to the natural history of retinal degeneration in the rhodopsin mutant dogs means that now we can test new treatments for value and safety before attempting the same in human patients.”

When the investigators used lower light exposure levels, the degeneration process was slower and lasted six months or longer. Even further lowering of light exposure resulted in retinal injury that could be repaired over a period of weeks to months.

“It is tempting to speculate that extremely slow recovery of vision following light exposure observed in patients with rhodopsin mutations may represent the human equivalent of retinal repair mechanisms observed in the rhodopsin mutant dogs,” says Cideciyan. “Better understanding of the components of this repair mechanism may lead to new treatment strategies based on augmentation of innate repair.”

“The potentially damaging effects of environmental light have been well-studied and discussed in the past,” adds Jacobson. “Now, we have clues that a specific subgroup of patients may be far more vulnerable to light than others. These patients should be identified clinically and by gene testing and then counseled about this vulnerability. A clinical trial is definitely indicated.”

The research from the Penn-Cornell investigators ushers in a new era of eye-disease prevention by considering the interaction of genetics and environment - in this case exposure to light - on an individual basis. The investigators recommend that all patients with the clinical diagnosis of RP should see an RP specialist to determine their family pattern (the every generation or dominant form is the vulnerable one), their eye disease pattern by specialized (low-light level) testing, and the genetic cause of their RP to know whether this research applies to them and their family members.

Other members of the research team are Tomas Aleman, Alexander Sumaroka, and Danian Gu from Penn, as well as Susan Pearce-Kelling from Cornell. The research was sponsored by the National Eye Institute of the National Institutes of Health, Foundation Fighting Blindness, Macula Vision Research Foundation, F.M. Kirby Foundation, Macular Disease Foundation, Research to Prevent Blindness, Mackall Foundation, ONCE International Prize from Spain, and the Van Sloun Fund.